Insulin signal transduction is a multiple-step process and defects in insulin signaling in cells might result in insulin resistance, as occurs in NIDDM. The overall goal of this proposal is to learn more about the proteins involved in insulin signal transduction and regulation, while focusing on the newly identified insulin receptor binding protein Grb-IR (for Insulin Receptor associated Growth factor receptor binding protein) and its Pleckstrin-homology (PH) domain-containing isoform Grb-IRPH. Of interest are the observations that only Grb-IRPH undergoes insulin-stimulated phosphorylation and that the expression of Grb-IR in cells inhibits insulin signaling, suggesting isoform-specific differences on insulin signal transduction. Aim 1 is to determine the roles of the Grb-IR isoforms in insulin signaling. Aim 2 is to characterize insulin-stimulated Grb-IRPH phosphorylation. Aim 3 is to identify and characterize proteins interacting with Grb-IR isoforms.